This proposal is designed to examine the relationships between structural brain abnormalities and both functional activation and cognitive deficits in schizophrenia. Anatomical abnormalities in regions such as the temporal cortex/hippocampus, the anterior cingulate (ACC), the prefrontal cortex (PFC), and the thalamus are a critical biological characteristic of schizophrenia. Many investigators have hypothesized that these structural abnormalities form the anatomical substrates of cognitive deficits in schizophrenia. Further, a growing functional imaging literature demonstrates that patients with schizophrenia exhibit activation disturbances in many of these same cortical regions during tasks that tap a range of cognitive processes, including working memory and long term memory encoding and recall. However, relatively little empirical evidence exists regarding the functional significance of brain structural abnormalities in schizophrenia. Thus, the goal of this project is to more clearly identify the relationship between particular brain structural characteristics and central functional activation and cognitive deficits in individuals with schizophrenia and those at risk for schizophrenia. To accomplish this goal, we will combine our cognitive challenge functional magnetic resonance imaging methods with state of the art structural imaging and high-dimensional brain mapping algorithms (Dr. Csernansky and Dr. Miller; Project 1). This will allow us to test the hypotheses that in schizophrenia: 1) deficits in both working memory and long term memory arise from a disturbance in a set of functionally and structurally interconnected brain regions that normally work together to support a range of cognitive processes; 2) structural disturbances in these regions are related to disturbances in the ability to functionally activate these areas during cognitive challenge; 2) deficits in these brain structures arise as a result of a neurodevelopmental process (Dr. Selemon, Project 3), and are thus present in individuals genetically at risk for schizophrenia (Dr. Clonninger, Project 1). The project outlined in this proposal has the potential to provide a unifying framework in which to understand the often seemingly bewildering array of cognitive and functional activation deficits that appear to be present in schizophrenia, and to understand the relationships of these disturbances to abnormalities present at the structural level. Success in this work would represent a significant advance in both our theoretical and empirical efforts, and could provide the groundwork for the development of powerful probes for detecting bio-behavioral and genetic risk markers for the development of schizophrenia.